Project Summary: Individuals with Down syndrome (DS), are paradoxically predisposed to certain autoimmune conditions including celiac disease, but spared from other conditions such as solid malignancies. The mechanism for the higher prevalence of celiac disease in DS remains unknown. Undiagnosed and untreated celiac disease impairs nutrition and can have lifelong impacts on bone health, fertility, cancer risk, growth, mental health, and mortality. Signs and symptoms of celiac disease may be masked in the DS population and adherence to the only current treatment, a strict gluten-free diet, is difficult. This proposal leverages the INCLUDE-funded Human Trisome Project (HTP), a large cohort study of individuals with DS using pan-omics approaches, to study the molecular signatures of celiac disease in DS. The long term goal is to utilize pan-omics data to gain a better fundamental understanding of the pathogenesis and potential biomarkers of celiac disease in those with and without DS. The central hypothesis is that there is a novel pan-omics signature for celiac disease in those with DS. This hypothesis will be tested with three specific research aims: 1) Compare the molecular signature of those with DS enrolled in the HTP with and without celiac disease 2) Collect proteomics and metabolomics from children without DS and with and without celiac disease to determine if the same molecular signatures of celiac disease are conserved in those without DS 3) Explore the impact of genetic risk alleles on celiac disease in DS. This proposal also supports career development aims geared to building the necessary skills for independent research funding in celiac disease and DS personalized medicine. This plan will prepare the trainee with the following four specific career development aims: 1) Develop skills needed to analyze multi-omics data 2) Learn to manage a research team 3) Learn applications of biomarker development 4) Prepare for career independence. The approach is innovative because it uses innovative data analysis techniques for multi-omics data to gain a deeper understanding of celiac disease in DS. The proposed research is significant because understanding the molecular signatures of celiac disease may enable the future development of improved diagnostic, therapeutic, and preventative strategies in those with DS and for the general population.